tbuckley/cabot-search huggingface dataset:
Abstract 3796: Deeper insight into intratumoral heterogeneity by MRI and PET-guided stereotactic biopsies from glioblastoma patients
Authors: Atul Anand, Jeanette Krogh Petersen, Mark Burton, Martin Jakob Larsen, Lars van Andersen, Dylan Scott Harwood, Christian Bonde Pedersen, Frantz Rom Poulsen, Peter Grupe, Torben A. Kruse, Mads Thomassen, Bjarne Winther Kristensen
Journal: Cancer Research (2022)

Abstract Glioblastoma is one of the most aggressive cancers, but the molecular evolution is not fully understood. We used PET imaging combined with deep sequencing of glioblastoma biopsies at both the RNA and DNA levels to get a deeper insight into molecular evolution. In the clinical setting, PET imaging provides information about metabolically active tumor areas, but the molecular interpretation is unclear. Our primary objective was to perform an intratumoral spatial comparison of biopsies from potentially aggressive and less aggressive areas in glioblastomas according to PET scans. We used MRI co-registered with 11C-MET-PET (amino acid) and 18F-FDG PET (glucose) in order to obtain representative neurosurgical stereotactic biopsies from tumor areas with high accumulation of these two metabolites (hotspot), low accumulation (coldspot), and no accumulation as the periphery of six glioblastoma patients that were processed for whole genome, exome, and transcriptome sequencing. Differential gene expression and gene ontology analysis showed that hotspots were enriched in gene sets associated with DNA replication, cell cycle, and ligand-receptor interaction. Genome and exome analysis suggested hotspots and coldspots have similar mutational profiles. However, a limited number of hotspot-specific mutations and novel fusion transcripts indicated that hotspot-associated tumor cells developed from coldspot-associated tumor cells and point at the potential role of hotspot driver genes in glioblastoma evolution. Our findings reveal that hotspots in glioblastomas represent a more advanced stage of molecular evolution than coldspots. Citation Format: Atul Anand, Jeanette Krogh Petersen, Mark Burton, Martin Jakob Larsen, Lars van Andersen, Dylan Scott Harwood, Christian Bonde Pedersen, Frantz Rom Poulsen, Peter Grupe, Torben A. Kruse, Mads Thomassen, Bjarne Winther Kristensen. Deeper insight into intratumoral heterogeneity by MRI and PET-guided stereotactic biopsies from glioblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3796.
Abstract 759: Analytical performance of a novel next generation sequencing assay for myeloid MRD
Authors: Hua Zhang, Xinzhan Peng, Guobin Luo, Annie Kraltcheva, David Mandelman, Michelle Swimley, Eli Pazol, Jose Espinoza, Scott Mitchell, Bo Ding, Ratnesh Singh, Doug Fenger, Na Li, Andrew Hatch, Vadim Mozhayskiy, Steven Roman, Sophie Rozenzhak
Journal: Cancer Research (2022)

Abstract The detection of molecular measurable residual disease (MRD) for acute myeloid leukemia (AML) has shown promise as a prognostic for AML. To support clinical and translational research into potential strategies for MRD monitoring applications in the future, a next-generation sequencing (NGS) assay, the Oncomine Myeloid MRD Assay (RUO), was developed. This assay utilizes Unique Molecular Tags (UMT) and Ion AmpliSeq HD™ technology to detect ultra-low frequency genetic alterations from blood or bone marrow samples. The workflow includes manual AmpliSeq HD library construction, templating on Ion Chef™, and sequencing on Ion GeneStudio™ sequencers. The assay contains both DNA and RNA targeted panels to detect SNVs, indels, fusion markers, and microhaplotype. The DNA panel covers 1256 hotspots in 33 genes, including key mutations in NPM1, FLT3, DNMT3A and full gene coverage for CEBPA and TP53. The panel achieved a limit of detection (LOD) of 0.1% when tested on 27 reference genomic DNA samples and over 40 clinical research samples. The RNA panel detects 1003 fusion isoforms for 27 fusion driver genes, including BCR-ABL1, RUNX1, CBFB-MYH11, and KTM2A (MLL) partial tandem duplications (PTDs) and fusions. The assay also includes a Microhaplotyping panel to monitor chimerism. The workflow is analytically verified and includes an optimized analysis pipeline for sensitive and accurate MRD detection. Overall, this comprehensive Myeloid MRD (RUO) assay reliably identifies DNA mutations and fusions with high sensitivity and provides a new tool for myeloid MRD research. RUO: For Research Use Only. Not for use in diagnostic procedures. Citation Format: Hua Zhang, Xinzhan Peng, Guobin Luo, Annie Kraltcheva, David Mandelman, Michelle Swimley, Eli Pazol, Jose Espinoza, Scott Mitchell, Bo Ding, Ratnesh Singh, Doug Fenger, Na Li, Andrew Hatch, Vadim Mozhayskiy, Steven Roman, Sophie Rozenzhak. Analytical performance of a novel next generation sequencing assay for myeloid MRD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 759.
Abstract 385: iRGD mediated delivery of neoantigens to enable immunotherapy in integrin b5-rich tumors
Authors: Tatiana Hurtado de Mendoza, Evangeline S. Mose, Gregory P. Botta, Gary B. Braun, Venkata R. Kotamraju, Randall P. French, Kodai Suzuki, Norio Miyamura, Siming Sun, Jay Patel, Tambet Teesalu, Erkki Ruoslahti, Kazuki N. Sugahara, Andrew M. Lowy
Journal: Cancer Research (2022)

Abstract Pancreatic duct adenocarcinomas are known for their abundant desmoplastic stroma that acts as a barrier for drug penetration and reduces treatment efficacy. iRGD is a tumor-penetrating peptide that initially targets αv integrins expressed on tumor vasculature with its RGD motif and then is proteolytically processed to expose a CendR motif (R/KXXR/K) that interacts with neuropilin-1 (NRP-1), leading to extravasation. We investigated the mechanism of iRGD tissue penetration and found that iRGD initially targets Carcinoma Associated Fibroblasts (CAFs) and then spreads to the tumor cells in a time dependent manner. CAF targeting was dependent on integrin β5 expression and CAFs induced upregulation of integrin β5 in the adjacent tumor cells in a TGF- β dependent manner. Drugs conjugated or co-administered with iRGD can penetrate deep into tumor tissue, significantly increasing the efficacy of chemotherapeutic agents in a variety of solid tumors. Our recent data shows that KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre (KPC) mice treated with iRGD co-administered with Gemcitabine increased survival compared to drug alone. In addition, we are using iRGD to deliver neoantigens to breast and pancreatic cancers to enable immunotherapy. These tumors have a low mutational burden and a very immunosuppressive microenvironment, rendering them resistant to such therapies. We have used iRGD, to deliver the ovalbumin 257-264 (OVAI) peptide to triple negative breast tumors, followed by adoptive T cell transfer of OT1 CD8 T cells, in order to elicit an antitumor immune response. Our preliminary data showed tumor regression in 70%, and complete response in 42% of the mice treated with iRGD plus OVA1. We are now working on adapting this strategy to pancreatic cancer. Citation Format: Tatiana Hurtado de Mendoza, Evangeline S. Mose, Gregory P. Botta, Gary B. Braun, Venkata R. Kotamraju, Randall P. French, Kodai Suzuki, Norio Miyamura, Siming Sun, Jay Patel, Tambet Teesalu, Erkki Ruoslahti, Kazuki N. Sugahara, Andrew M. Lowy. iRGD mediated delivery of neoantigens to enable immunotherapy in integrin b5-rich tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 385.
Abstract 6285: MicroRNA-217 affects tumor microenvironment and enhances the chemosensitivity of pancreatic cancer
Authors: Yuki Kaneko, HIdeyuki Ohzawa, Yuki Kimura, Kohei Tamura, Yurie Futoh, Kazuya Takahashi, Akira Saito, Mineyuki Tojo, Hideyo Miyato, Naohiro Sata, Joji Kitayama
Journal: Cancer Research (2022)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and an inherently chemoresistant tumor. Dense fibrotic stroma is a major obstacle for drug delivery to the tumor cells in PDAC. Pancreatic stellate cells (PSCs) are the major stromal cells responsible for fibrotic microenvironment. MicroRNA-217 (miR-217) is known mainly as a tumor suppressor. However, the detailed roles of miR-217 on pathophysiology of PDAC remain unclarified. Methods: Expressions levels of miR-217 were measured in surgically resected human PDAC samples. Using Lipofectamine RNAiMAX, miR-217 or negative control miR (NC) were transfected in human pancreatic cancer cells, Panc-1, MIApaca-2, BxPC-3 and murine PAN02 cells, and chemosensitivities to gemcitabine and paclitaxel were investigated by MTS assay. Human hPSC-1 (obtained from Riken cell bank, Japan) was cultured in 20%FBS+DMEM and the changes of phenotypes and expression levels of miR-217 after the stimulation with TGF-β1 was measured by fluorescein microscope and digital PCR, respectively. Results: The expression level of miR-217 was markedly downregulated in PDAC tissues than in noncancerous pancreatic tissues (P&amp;lt;0.001, n=9). Overexpression of miR-217 significantly inhibited the proliferation of Panc-1, MIApaca-2 and BxPC-3 (P&amp;lt;0.001) and migration of Panc-1, MIApaca-2 and PAN02 (P&amp;lt;0.05). Lipofection of miR-217 further reduced the number of PAN02 exposed to 1-5nM gemcitabine (P&amp;lt;0.0001) and 0.01-0.1uM paclitaxel (P=0.0085) which resulted in the reduced the IC-50 as compared with NC. Human PSC-1 stimulated with TGF-β1 (10ng/ml) significantly reduced miR-217 expression compared to nascent cells. The stimulation with TGF-β1 upregulated the expression of cancer associated fibroblast (CAF) markers, α-smooth muscle actin (SMA) and vimentin. However, the expression levels of these markers were significantly reduced by the kipofection of miR-217. Conclusion: MiR-217 affects both cancer and stromal cells in PDAC which may regulate chemosensitivity in PDAC. Restoring miR-217 levels in tumor cells and/or PSCs could be a future therapeutic strategy. Citation Format: Yuki Kaneko, HIdeyuki Ohzawa, Yuki Kimura, Kohei Tamura, Yurie Futoh, Kazuya Takahashi, Akira Saito, Mineyuki Tojo, Hideyo Miyato, Naohiro Sata, Joji Kitayama. MicroRNA-217 affects tumor microenvironment and enhances the chemosensitivity of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6285.
Abstract SY23-01: Targeting the reciprocal interplay between inflammation, fibrosis, and pro-tumor immunity
Authors: Valerie M. Weaver
Journal: Cancer Research (2022)

Abstract Tumors are characterized by increased levels of remodeled and crosslinked extracellular matrix (ECM) proteins that progressively stiffen the tissue stroma. Transformed cells exhibit a perturbed oncogene-stimulated and ECM-tuned mechanophenotype that further stimulates ECM remodeling and stiffening. We have been exploring how these aberrant cell and tissue level forces arise and by what means these forces contribute to malignancy and metastasis, and how they promote tumor recurrence and treatment resistance. We use two and three dimensional culture models with tuned ECM stiffness, as well as transgenic and syngeneic mouse models, human PDX models and human biospecimens, in which ECM crosslinking and stiffness and integrin mechanosignaling are manipulated and quantified. Our work has thus far revealed that the tumor ECM is progressively remodeled, and stiffened, primarily by stromal fibroblasts. We determined that infiltrating pro-tumorigenic myeloid cells secrete factors that stimulate stromal fibroblasts to remodel and crosslink the ECM and that this occurs quite early during tumor evolution. The stromal-fibroblast stiffened ECM thereafter disrupts tissue organization, promotes cell growth and survival and drives cell invasion. The stiffened tumor stroma additionally drives angiogenesis, and activates STAT3 to increase expression of cytokines and chemokines that further stimulate immune cell infiltration. The stiffened ECM thereafter reprograms the infiltrating myeloid cells by altering integrin adhesions and TGFβ SMAD signaling to induce an ECM synthetic metabolic phenotype in the myeloid cells. The metabolically reprogrammed myeloid cells ultimately compromise arginine tissue availability and increase tissue levels of ornithine that severely disrupt CD8 T cell tissue infiltration and perturb their anti-tumor function to accelerate tumor aggression and metastatic dissemination. I will discuss the dynamic and reciprocal interplay between tissue tension and innate and acquired immunity. I will then present data to show how ECM stiffness is able to promote tumor aggression and metastasis by dysregulating anti-tumor immunity. I will end with a short discussion regarding approaches to design therapies informed by these results to improve cancer treatment. Citation Format: Valerie M. Weaver. Targeting the reciprocal interplay between inflammation, fibrosis, and pro-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY23-01.
Abstract 1999: The impact of the COVID-19 pandemic on 30-day survival in pediatric cancer patients in low, middle, and high-income countries: an international, observational cohort study
Authors: Muhammed Elhadi, Soham Bandyopadhyay, Noel Peter, Kokila Lakhoo
Journal: Cancer Research (2022)

Abstract Objectives: To conduct the first international cohort study to ascertain the short-term outcome for pediatric oncology patients who underwent treatment across 16 high-income countries (HICs) and 23 low- and- middle-income countries (LMICs) during the COVID-19 pandemic. The hypotheses being tested was that the COVID-19 pandemic had affected paediatric cancer care, and that the outcomes of children were worse in LMICs. Design: A multicenter, international, collaborative cohort study. Setting: 91 hospitals and cancer centers in 39 countries providing cancer treatment to pediatric patients between March and December 2020. Participants: Patients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukemia, Non-Hodgkin lymphoma, Hodgkin lymphoma, Wilms Tumor, Sarcoma, Retinoblastoma, Gliomas, Medulloblastomas or Neuroblastomas, in keeping with the World Health Organization Global Initiative for Childhood Cancer. Main outcome measure: All-cause mortality at 30 days and 90 days. Results: 1660 patients were recruited. Over 30 days, 45 LMIC patients (4.3%; 95% CI: 3.1 to 5.5) and 2 HIC patients (0.4%; 95% CI: -0.1 to 0.9) died. 219 children had their treatments delayed, interrupted, or modified. LMIC patients had 11.7 (95% CI: 10.3 to 13.1) and 7.4 (95% CI: 6.5 to 8.3) times the risk of death at 30 days and 90 days respectively (p &amp;lt; 0.001). After adjusting for confounders, pediatric cancer patients in LMICs had 35.7 times the odds of death at 30 days (p &amp;lt; 0.001). Conclusions: The COVID-19 pandemic has affected pediatric oncology service provision. It has disproportionately affected patients in LMICs, highlighting and compounding existing disparities in healthcare systems globally that need addressing urgently. However, most pediatric cancer patients continued to receive their normal standard of care. This speaks to the adaptability and resilience of health-care systems and healthcare workers globally. Citation Format: Muhammed Elhadi, Soham Bandyopadhyay, Noel Peter, Kokila Lakhoo, Global Children's NCDs Collaborative. The impact of the COVID-19 pandemic on 30-day survival in pediatric cancer patients in low, middle, and high-income countries: an international, observational cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1999.
Abstract 2664: Development of covalent <i>KRASG12C</i> inhibitor APG-1842 for the treatment of solid tumors
Authors: Shaoulai Gu, Qiang Li, Chao Li, Qixin Wang, Douglas D. Fang, Shaomeng Wang, Dajun Yang, Yifan Zhai
Journal: Cancer Research (2022)

Abstract The KRAS gene, which encodes a guanosine triphosphate (GTPase) protein, is frequently mutated in solid cancers. The KRASG12C mutation aberrantly attenuates GTPase activity, leading to accumulation of the GTP-bound activated form of the KRAS protein and activation of downstream signaling pathways. This genotype occurs in approximately 13% of non-small-cell lung cancers (NSCLCs) and 1% to 3% of colorectal cancers and other solid tumors. In this study, investigational agent APG-1842 was characterized as a potent, selective, and covalent KRASG12C inhibitor that irreversibly and specifically blocks KRASG12C in an inactive guanosine diphosphate (GDP)-bound state and downregulates KRAS-dependent signaling. A RAS-GTP pull-down assay demonstrated that APG-1842 (at a concentration as low as 12 nM) completely blocked GDP-GTP nucleotide exchange, which stabilized an inactive GDP-bound form of KRASG12C and thereby inhibited RAS and RAF binding in KRASG12C-mutant human NSCLC NCI-H358 cells. In these cells, APG-1842 dose dependently inhibited KRAS-dependent signaling target proteins, including phosphorylated extracellular signal-regulated kinase (ERK), S6, and serine/threonine protein kinase Akt (protein kinase B), with a half-maximal inhibitory concentration (IC50) value of 4 nM for ERK1/2 phosphorylation. Using a panel of 18 cancer cell lines representing multiple cancer types in cell viability assays, we found that APG-1842 selectively inhibited cell proliferation in KRASG12C-mutated, but not non-KRASG12C or KRAS wild-type, cell lines. Oral APG-1842 in mice carrying cell-derived NCI-H358 NSCLC subcutaneous xenografts exerted significant antitumor efficacy at doses ranging from 3 to 100 mg/kg, resulting in tumor regression at 30 mg/kg and above. Consistent with the cellular results, APG-1842 dose dependently inhibited ERK1/2 and S6 phosphorylation in xenografts after 6 and 24 hours of treatment, correlating with systemic and tumor drug exposures. Significant antitumor activity of APG-1842 was also confirmed in a panel of 8 KRASG12C-mutated patient-derived xenograft models derived from patient samples of lung, colorectal, and gastric cancers. Collectively, these preclinical results suggest that APG-1842 is a potent, bioavailable, and highly selective KRASG12C inhibitor, laying a foundation for clinical development of this agent for patients with KRASG12C-mutant solid tumors. Citation Format: Shaoulai Gu, Qiang Li, Chao Li, Qixin Wang, Douglas D. Fang, Shaomeng Wang, Dajun Yang, Yifan Zhai. Development of covalent KRASG12C inhibitor APG-1842 for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2664.
Abstract 602: 23ME-00610 is a first-in-class monoclonal antibody that targets the CD200R1 immune checkpoint to enhance T cell-mediated antitumor activity
Authors: Jill Fenaux, Yao-ming Huang, Cristina Melero, Wei-Jen Chung, Suk Lee, Dina Ayupova, Mauro Poggio, Dylan Glatt, Zuoan Yi, Cecilia Lay, Maike Schmidt, Sophia R. Majeed, Germaine Fuh, Alice Chen, Sushil Kumar
Journal: Cancer Research (2022)

Abstract In the 23andMe genetic database, associations were observed for CD200R1 variants and autoimmune and cancer traits with opposing directionality. These data suggest that CD200R1 may be a pivotal checkpoint in immunosurveillance of cancer and a promising therapeutic target. CD200R1 is expressed widely on human T cells and myeloid cells; and binds to its cognate ligand CD200 to suppress the activity of immune cells. Elevated expression of CD200R1 was observed on tumor-infiltrating lymphocytes relative to peripheral blood mononuclear cells (PBMCs) from cancer patients. While the expression of CD200R1 and its ligand CD200 are well characterized, the downstream immunosuppressive role for CD200R1 in human tumors or the potentiation of anti-tumor T cell function by targeting of CD200R1 is not well understood. To test the therapeutic potential of inhibiting the CD200R1 pathway we developed 23ME-00610, a fully humanized monoclonal antibody that binds to all functionally relevant isoforms and haplotypes of CD200R1 with high affinity (KD values &amp;lt; 0.1 nM), to target tumors that are reliant on the CD200R1 immunosuppressive pathway. 23ME-00610 completely displaced the ligand CD200 from CD200R1 in cell-based flow cytometry assays with blocking IC50 values that ranged from 0.32 to 1.04 nM depending on the concentration of CD200 ligand present, and inhibited downstream signaling through the adaptor protein DOK2 in a reporter-based assay. Functionally, 23ME-00610 reversed CD200-mediated suppression of chronically stimulated primary T cells. In addition, 23ME-00610 enhanced PBMC-mediated tumor killing with a mean EC50 of 2.09 nM using methods of real-time measurement of cytotoxicity of human CD200-expressing tumor cells when compared to control antibodies. Moreover, 23ME-00610 promoted IFNγ production, a key functional anti-tumor T cell cytokine, in cancer patients’-derived PBMCs. Taken together, these results demonstrate that 23ME-00610 has the potential to reverse CD200-mediated immunosuppression in the TME to enhance anti-tumor T-cell functions in cancer patients. Citation Format: Jill Fenaux, Yao-ming Huang, Cristina Melero, Wei-Jen Chung, Suk Lee, Dina Ayupova, Mauro Poggio, Dylan Glatt, Zuoan Yi, Cecilia Lay, Maike Schmidt, Sophia R. Majeed, Germaine Fuh, Alice Chen, Sushil Kumar. 23ME-00610 is a first-in-class monoclonal antibody that targets the CD200R1 immune checkpoint to enhance T cell-mediated antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 602.